DESCRIPTION

REBIF (interferon beta-1a) is a purified 166 amino
acid glycoprotein with a molecular weight of approximately 22,500 daltons. It
is produced by recombinant DNA technology using genetically engineered Chinese
Hamster Ovary cells into which the human interferon beta gene has been introduced.
The amino acid sequence of REBIF is identical to that of natural fibroblast
derived human interferon beta. Natural interferon beta and interferon beta-1a
(REBIF) are glycosylated with each containing a single N-linked complex
carbohydrate moiety.

Using a reference standard calibrated against the World
Health Organization natural interferon beta standard (Second International
Standard for Interferon, Human Fibroblast GB 23 902 531), REBIF has a specific
activity of approximately 270 million international units (MIU) of antiviral activity
per mg of interferon beta-1a determined specifically by an in vitro cytopathic
effect bioassay using WISH cells and Vesicular Stomatitis virus. REBIF 8.8 mcg,
22 mcg and 44 mcg contains approximately 2.4 million international units, 6
million international units or 12 million international units, respectively, of
antiviral activity using this method.

INDICATIONS

REBIF (interferon beta-1a) is indicated for the
treatment of patients with relapsing forms of multiple sclerosis to decrease
the frequency of clinical exacerbations and delay the accumulation of physical
disability.

DOSAGE AND ADMINISTRATION

Dosing Information

The recommended dose of REBIF is either 22 mcg or 44 mcg
injected subcutaneously three times per week. REBIF should be administered, if
possible, at the same time (preferably in the late afternoon or evening) on the
same three days (e.g., Monday, Wednesday, and Friday) at least 48 hours apart
each week.

Generally, patients should be started at 20% of the
prescribed dose three times per week and increased over a 4-week period
to the targeted dose, either 22 mcg three times per week (see Table 1) or 44
mcg three times per week (see Table 2). Patients prescribed a targeted dose of 22
mcg three times per week should use the prefilled syringes for titration.

A Titration Pack containing 6 doses of 8.8 mcg (0.2 mL)
and 6 doses of 22 mcg (0.5 mL) is available for use during the titration period
in both REBIF prefilled syringes and REBIF Rebidose autoinjectors.

Table 1: Titration Schedule for a 22 mcg Prescribed
Dose*

Week of Use

Dose

Syringe to Use

Amount of syringe

Week 1 Titration

4.4 mcg

8.8 mcg syringe

Use half of syringe

Week 2 Titration

4.4 mcg

8.8 mcg syringe

Use half of syringe

Week 3 Titration

11 mcg

22 mcg syringe

Use half of syringe

Week 4 Titration

11 mcg

22 mcg syringe

Use half of syringe

Week 5 and after

22 mcg

22 mcg syringe or autoinjector

Use full syringe or autoinjector

*Use only prefilled syringes, not autoinjectors, to
titrate to the 22 mcg Prescribed Dose

Table 2: Titration Schedule for a 44 mcg Prescribed Dose**

Week of Use

Dose

Syringe or Autoinjector to Use

Amount of syringe or autoinjector

Week 1 Titration

8.8 mcg

8.8 mcg syringe or autoinjector

Use full syringe or autoinjector

Week 2 Titration

8.8 mcg

8.8 mcg syringe or autoinjector

Use full syringe or autoinjector

Week 3 Titration

22 mcg

22 mcg syringe or autoinjector

Use full syringe or autoinjector

Week 4 Titration

22 mcg

22 mcg syringe or autoinjector

Use full syringe or autoinjector

Week 5 and after

44 mcg

44 mcg syringe or autoinjector

Use full syringe or autoinjector

**Prefilled syringes or autoinjectors can be used to titrate
to the 44 mcg Prescribed Dose

Important Administration Instructions

REBIF is intended for use under the guidance and
supervision of a physician. It is recommended that physicians or qualified
medical personnel train patients in the proper technique for selfadministering subcutaneous
injections using the prefilled syringe or injection device approved for use
with REBIF. Injection depth of the REBIF Rebidose autoinjector is fixed at 8
mm; the healthcare provider should determine the injection technique.

The initial injection should be performed under the
supervision of an appropriately qualified healthcare provider.

Appropriate instruction for self-injection or
injection by another person should be provided to the patient or their
caregiver, including careful review of the REBIF Medication Guide and the REBIF
Rebidose autoinjector Instructions for Use that accompanies the product. Users
should demonstrate competency in all aspects of the injection prior to
independent use. If a patient isto self-administer REBIF, the physical
and cognitive ability of that patient to self-administer and properly
dispose of prefilled syringes or the REBIF Rebidose autoinjectors should be
assessed.

Patients with severe neurological deficits should not
self-administer injections without assistance from a trained caregiver.

REBIF Rebidose (interferon beta-1a) 44 mcg
Autoinjector

REBIF should be stored refrigerated between 36°F
to 46°F (2°C to 8°C). DO NOT FREEZE. If needed, REBIF may
be stored between 36°F to 77°F (2°C to 25°C) for up
to 30 days and away from heat and light, but refrigeration is preferred.

Do not use beyond the expiration date printed on
packages. REBIF contains no preservatives. Each prefilled syringe and REBIF
Rebidose autoinjector is intended for a single dose. Unused portions should be
discarded.

Clinical Trial Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of
REBIF cannot be directly compared to rates in the clinical trials of other
drugs and may not reflect the rates observed in practice.

A total of 712 patients with relapsing-remitting
multiple sclerosis (RRMS) in two controlled clinical trials took REBIF (22 mcg
or 44 mcg given three times per week) [see Clinical Studies]. Ages
ranged from 18 to 55 years. Nearly three-fourths of the patients were
female, and more than 90% were Caucasian, largely reflecting the general
demographics of the population of patients with multiple sclerosis.

Study 1 was a 2-year placebo-controlled study
in RRMS patients treated with REBIF 22 mcg(n=189), 44 mcg (n=184), or placebo
(n=187). Table 3 enumerates adverse reactions and laboratory abnormalities that
occurred at an incidence that was at least 2% more in either REBIF-treated
group than was observed in the placebo group.

Table 3: Adverse Reactions and Laboratory
Abnormalities in Study 1

Body System
Preferred Term

Placebo tiw
(n=187)
%

REBIF 22 mcg tiw
(n=189)
%

REBIF 44 mcg tiw
(n=184)
%

BODY AS A WHOLE

Influenza-like symptoms

51

56

59

Headache

63

65

70

Fatigue

36

33

41

Fever

16

25

28

Rigors

5

6

13

Chest pain

5

6

8

Malaise

1

4

5

INJECTION SITE DISORDERS

Injection Site Reaction

39

89

92

Injection Site Necrosis

0

1

3

NERVOUS SYSTEM DISORDERS

Hypertonia

5

7

6

Coordination Abnormal

2

5

4

Convulsions

2

5

4

Somnolence

1

4

5

ENDOCRINE DISORDERS

Thyroid Disorder

3

4

6

GASTROINTESTINAL SYSTEM DISORDERS

Abdominal Pain

17

22

20

Dry Mouth

1

1

5

LIVER AND BILIARY SYSTEM DISORDERS

SGPT Increased

4

20

27

SGOT Increased

4

10

17

Bilirubinemia

1

3

2

MUSCULO-SKELETAL SYSTEM DISORDERS

Myalgia

20

25

25

Back Pain

20

23

25

Skeletal Pain

10

15

10

HEMATOLOGIC DISORDERS

Leukopenia

14

28

36

Lymphadenopathy

8

11

12

Thrombocytopenia

2

2

8

Anemia

3

3

5

SKIN DISORDERS

Rash Erythematous

3

7

5

Rash Maculo-Papular

2

5

4

Hyperhidrosis

2

4

4

URINARY SYSTEM DISORDERS

Micturition Frequency

4

2

7

Urinary Incontinence

2

4

2

VISION DISORDERS

Vision Abnormal

7

7

13

Xerophthalmia

0

3

1

Adverse reactions in Study 2, a 1-year active-controlled
(vs. interferon beta-1a, 30 mcg once weekly intramuscular injection,
n=338) study including 339 patients with MS treated with REBIF were generally
similar to those in Study 1, taking into account the disparity in study
durations.

Immunogenicity

Anaphylaxis and other allergic reactions have been
observed with the use of REBIF [see WARNINGS AND PRECAUTIONS]. As with
all therapeutic proteins, there is a potential for immunogenicity. In Study 1,
the presence of neutralizing antibodies (NAb) to REBIF was determined by
collecting and analyzing serum pre-study and at 6 month time intervals
during the 2 years of the clinical trial. Serum NAb were detected in 59/189
(31%) and 45/184 (24%) of REBIF-treated patients at the 22 mcg and 44 mcg
three times per week doses, respectively, at one or more times during the
study. The data reflect the percentage of patients whose test results were
considered positive for antibodies to REBIF using an antiviral cytopathic
effect assay, and are highly dependent on the sensitivity and specificity of
the assay. Additionally, the observed incidence of NAb positivity in an assay
may be influenced by several factors including sample handling, timing of
sample collection, concomitant medications and underlying disease. For these
reasons, comparison of the incidence of antibodies to REBIF with the incidence
of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified
during post-approval use of REBIF. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.

DRUG INTERACTIONS

No information provided.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Depression and Suicide

REBIF (interferon beta-1a) should be used with
caution in patients with depression, a condition that is common in people with
multiple sclerosis. Depression, suicidal ideation, and suicide attempts have
been reported to occur with increased frequency in patients receiving
interferon compounds, including REBIF. In addition, there have been
postmarketing reports of suicide in patients treated with REBIF. Patients
should be advised to report immediately any symptoms of depression and/or
suicidal ideation to the prescribing physician. If a patient develops depression,
cessation of treatment with REBIF should be considered.

Hepatic Injury

Severe liver injury, including some cases of hepatic
failure requiring liver transplantation, has been reported rarely in patients
taking REBIF. Symptoms of liver dysfunction began from one to six months
following the initiation of REBIF. If jaundice or other symptoms of liver
dysfunction appear, treatment with REBIF should be discontinued immediately due
to the potential for rapid progression to liver failure.

Asymptomatic elevation of hepatic transaminases
(particularly SGPT) is common with interferon therapy [see ADVERSE REACTIONS].
REBIF should be initiated with caution in patients with active liver disease,
alcohol abuse, increased serum SGPT ( > 2.5 times ULN), or a history of significant
liver disease. Also, the potential risk of REBIF used in combination with known
hepatotoxic products should be considered prior to REBIF administration, or
when adding new agents to the regimen of patients already on REBIF. Reduction
of REBIF dose should be considered if SGPT rises above 5 times the upper limit
of normal. The dose may be gradually re-escalated when enzyme levels have
normalized [see Laboratory Tests; and DOSAGE AND ADMINISTRATION].

Anaphylaxis And Other Allergic Reactions

Anaphylaxis has been reported as a rare complication of
REBIF use. Other allergic reactions have included skin rash and urticaria, and
have ranged from mild to severe without a clear relationship to dose or
duration of exposure. Several allergic reactions, some severe, have occurred
after prolonged use. Discontinue REBIF if anaphylaxis occurs.

Injection Site Reactions Including Necrosis

In controlled clinical trials, injection site reactions
occurred more frequently in REBIF-treated patients (92% in the 44 mcg
group and 89% in the 22 mcg group) than in placebo-treated patients (39%)
and at a higher frequency in REBIF treated patients (83%) than in AVONEX treated
patients (28%). Injection site necrosis also occurred more frequently in REBIF-treated
patients (3% in the 44 mcg group and 1% in the 22 mcg group) than in placebo-treated
patients (0) during the two years of therapy. All events resolved with
conservative management.

Injection site reactions including injection site pain,
erythema, edema, cellulitis, abscess, and necrosis have been reported in the
postmarketing setting. Some occurred more than 2 years after initiation of
REBIF. Necrosis occurred at single and at multiple injection sites. Some cases of
injection site necrosis required treatment with intravenous antibiotics and
surgical intervention (debridement and skin grafting).

Patient understanding and use of aseptic self-injection
techniques and procedures should beperiodically evaluated, particularly if
injection site necrosis has occurred. Patients should be advised of the
importance of rotating sites of injection with each dose and not reusing
syringes. Patients should be advised against injecting an area which is
inflamed, edematous, erythematous, ecchymotic, or has any other signs of
infection. These signs should be reported to a healthcare professional
immediately.

Decreased Peripheral Blood Counts

Decreased peripheral blood counts in all cell lines,
including pancytopenia, have been reported in REBIF-treated patients. In
controlled clinical trials, leukopenia occurred at a higher frequency in REBIF-treated
patients (36% in 44 mcg group and 28% in 22 mcg group) than in placebotreated patients
(14%) and at a higher frequency in REBIF-treated patients (6%) compared
to the AVONEX-treated patients ( < 1%). Thrombocytopenia and anemia
occurred more frequently in 44 mcg REBIF-treated patients (8% and 5%,
respectively) than in placebo-treated patients (2% and 3%, respectively).
In a pooled analysis of 7 placebo controlled trials with REBIF doses of 22 mcg or
44 mcg, the rate of pancytopenia (in subjects with normal baseline values who
developed laboratory values less than the lower limit of normal for all 3
hematology parameters simultaneously) was higher in the total REBIF group (5.5
per 1000 subject-year) than in the placebo group (1.2 per 1000 subject-year).
Patients should be monitored for symptoms or signs of decreased blood counts.
Monitoring of complete blood and differential white blood cell counts is also
recommended [see DOSAGE AND ADMINISTRATION and Laboratory Tests].

Thrombotic Microangiopathy

Cases of thrombotic microangiopathy (TMA), including
thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal,
have been reported with interferon beta products, including REBIF. Cases have
been reported several weeks to years after starting interferon beta products.
Discontinue REBIF if clinical symptoms and laboratory findings consistent with
TMA occur, and manage as clinically indicated.

Seizures

Caution should be exercised when administering REBIF to
patients with pre-existing seizure disorders. Seizures have been
temporally associated with the use of beta interferons, including REBIF, in
clinical trials and in postmarketing reports.

Laboratory Tests

In addition to those laboratory tests normally required
for monitoring patients with multiple sclerosis, blood cell counts and liver
function tests are recommended at regular intervals (1, 3, and 6 months)
following introduction of REBIF therapy and then periodically thereafter in the
absence of clinical symptoms. Patients with myelosuppression may require more
intensive monitoring of complete blood cell counts, with differential and
platelet counts [see DOSAGE AND ADMINISTRATION and Decreased Peripheral Blood Counts]. New or worsening thyroid abnormalities have developed in some
patients treated with REBIF. Thyroid function tests are recommended every 6
months in patients with a history of thyroid dysfunction or as clinically indicated.

Patient Counseling Information

Inform patients of the availability of a Medication
Guide, and instruct them to read the Medication Guide prior to taking REBIF.
Instruct patients to take REBIF only as prescribed.

Depression and Suicide

Advise patients that depression, suicidal ideation, and
suicide have been reported during the use of REBIF. Inform patients of the
symptoms of depression and suicidal ideation and instruct patients to
immediately report any of these symptoms to their healthcare provider [see WARNINGS
AND PRECAUTIONS].

Hepatic Injury

Advise patients that severe liver injury, including
hepatic failure, has been reported with the use of REBIF. Educate patients
about the symptoms of hepatic injury and instruct patients to report them
immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Anaphylaxis and Other Allergic Reactions

Advise patients of the symptoms of allergic reactions and
anaphylaxis, and instruct patients to seek immediate medical attention if these
symptoms occur [see WARNINGS AND PRECAUTIONS].

Injection Site Reactions including Necrosis

Advise patients that injection site reactions occur in
most patients treated with REBIF and that injection site necrosis may occur [see
WARNINGS AND PRECAUTIONS]. Instruct patients to promptly report any
break in the skin, which may be associated with blue-black discoloration,
swelling, or drainage of fluid from the injection site, prior to continuing
their REBIF therapy.

To minimize the likelihood of injection site reactions,
inform patients of the importance of rotating injection sites with each dose
and the use of aseptic injection technique [see DOSAGE AND ADMINISTRATION].
Advise patients not to re-use needles or syringes and instruct patients
on safe disposal procedures. Provide appropriate instruction for self-injection
of REBIF and REBIF Rebidose, including careful review of the REBIF Medication
Guide.

Decreased Peripheral Blood Counts

Advise patients that they may develop a lowering of their
peripheral blood counts, including their white blood counts, red blood counts,
and platelets, and that their blood counts will be checked during therapy with
REBIF. Inform patients that they may be more likely to get infections, anemia,
or be at risk for bleeding, and that they should contact their healthcare provider
if they develop symptoms of these adverse reactions [see WARNINGS AND
PRECAUTIONS].

Seizures

Flu-like Symptoms

Inform patients that flu-like symptoms are common
following initiation of therapy with REBIF. Advise patients that concurrent use
of analgesics and/or antipyretics may help reduce flu-like symptoms on
treatment days [see DOSAGE AND ADMINISTRATION].

Risk in Pregnancy

Advise patients that REBIF should not be used during
pregnancy unless the potential benefit justifies the potential risk to the
fetus [see Use In Specific Populations]. Therefore, inform patients that
if a pregnancy is considered, or does occur, the risks and benefits of
continuing REBIF should be discussed with their healthcare provider.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Mutagenesis

Interferon beta was negative in an in vitro bacterial
reverse mutation (Ames) assay and an in vitro cytogenetic assay in human
lymphocytes in the presence and absence of metabolic activation.

Impairment of Fertility

In studies in normally cycling female cynomolgus monkeys
given daily subcutaneous injections of interferon beta for six months at doses
of up to 9 times the recommended weekly human dose (based on body surface
area), no effects were observed on either menstrual cycling or serum estradiol
levels. In male monkeys, the same doses of interferon beta had no demonstrable
adverse effects on sperm count, motility, morphology, or function.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies
in pregnant women. REBIF should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.

In a study in pregnant cynomolgus monkeys, interferon
beta was administered daily (intramuscular doses approximately 1, 2, and 7
times the maximum recommended cumulative weekly human dose, based on body
surface area) either throughout the period of organogenesis or later in
pregnancy (gestation day 90 to term). No adverse effects on embryofetal development
were observed; however, the possibility of adverse effects cannot be ruled out because
of the small number of animals tested (six per dose group at each developmental
period).

Nursing Mothers

It is not known whether REBIF is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
REBIF is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not
been established.

Geriatric Use

Clinical studies of REBIF did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently than younger subjects. In general, dose selection for an elderly
patient should be cautious, usually starting at the low end of the dosing
range, reflecting the greater frequency of decreased hepatic, renal or cardiac
function, and of concomitant disease or other drug therapy.

Overdosage & Contraindications

OVERDOSE

No information provided.

CONTRAINDICATIONS

REBIF is contraindicated in patients with a history of
hypersensitivity to natural or recombinant interferon beta, human albumin, or
any other component of the formulation.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

The mechanism(s) by which REBIF (interferon beta-1a)
exerts its therapeutic effects in patients with multiple sclerosis is unknown.

Pharmacodynamics

The relationships between serum interferon beta-1a
levels and measurable pharmacodynamic activities to the mechanism(s) by which
REBIF exerts its effects in multiple sclerosis are unknown. No gender-related
effects on pharmacodynamic parameters have been observed.

Pharmacokinetics

The pharmacokinetics of REBIF (interferon beta-1a)
in people with multiple sclerosis have not been evaluated. In healthy subjects,
a single subcutaneous (sc) injection of 60 mcg of REBIF (liquid formulation)
resulted in a peak serum concentration (Cmax) of 5.1 ± 1.7 IU/mL (mean ± SD),
with a median time of peak serum concentration (Tmax) of 16 hours. The serum
elimination half-life (t½) was 69 ± 37 hours, and the area under the
serum concentration versus time curve (AUC) from zero to 96 hours was 294 ± 81
IU h/mL. Following every other day sc injections in healthy subjects, an
increase in AUC of approximately 240% was observed, suggesting that accumulation
of interferon beta-1a occurs after repeat administration. Total clearance
is approximately 33-55 L/hour. There have been no observed gender-related
effects on pharmacokinetic parameters. Pharmacokinetics of REBIF in pediatric
and geriatric patients or patients with renal or hepatic insufficiency have not
been established.

Clinical Studies

Two multicenter studies evaluated the safety and efficacy
of REBIF in patients with relapsingremitting multiple sclerosis.

Study 1 was a randomized, double-blind, placebo
controlled study in patients with multiple sclerosis for at least one year,
Kurtzke Expanded Disability Status Scale (EDSS) scores ranging from 0 to 5, and
at least 2 acute exacerbations in the previous 2 years. Patients with secondary
progressive multiple sclerosis were excluded from the study. Patients received
subcutaneous injections of either placebo (n = 187), REBIF 22 mcg (n = 189), or
REBIF 44 mcg (n = 184) administered three times per week for two years. Doses
of study agents were progressively increased to their target doses during the
first 4 to 8 weeks for each patient in the study [see DOSAGE AND
ADMINISTRATION].

The primary efficacy endpoint was the number of clinical
exacerbations. Numerous secondary efficacy endpoints were also evaluated and
included exacerbation-related parameters, effects of treatment on
progression of disability and magnetic resonance imaging (MRI)-related parameters.
Progression of disability was defined as an increase in the EDSS score of at
least one point sustained for at least 3 months. Neurological examinations were
completed every 3 months, during suspected exacerbations, and coincident with
MRI scans. All patients underwent proton density T2-weighted (PD/T2) MRI
scans at baseline and every 6 months. A subset of 198 patients underwent PD/T2
and T1-weighted gadolinium-enhanced (Gd)-MRI scans monthly
for the first 9 months. Of the 560 patients enrolled, 533 (95%) provided 2
years of data and 502 (90%) received 2 years of study agent.

Study results are shown in Table 4 and Figure 1. REBIF at
doses of 22 mcg and 44 mcg administered three times per week significantly
reduced the number of exacerbations per patient as compared to placebo.
Differences between the 22 mcg and 44 mcg groups were not significant (p
> 0.05).

The exact relationship between MRI findings and the
clinical status of patients is unknown. Changes in lesion area often do not
correlate with changes in disability progression. The prognostic significance
of the MRI findings in these studies has not been evaluated.

Table 4: Clinical and MRI Endpoints from Study 1

Placebo
n = 187

REBIF 22 mcg
n = 189

REBIF 44 mcg
n = 184

Exacerbation-related

Mean number of exacerbations per patient over 2 years1,2 (Percent reduction)

2.56

1.82**
(29%)

1.73***
(32%)

Percent (%) of patients exacerbation-free at 2 years3

15%

25%*

32%***

Median time to first exacerbation (months)1,4

4.5

7.6**

9 6***

MRI

n = 172

n = 171

n = 171

Median percent (%) change of MRI PD-T2 lesion area at 2 years5

11.0%

-1.2%***

-3.8%***

Median number of active lesions per patient per scan (PD/T2; 6 monthly)5

2.25

0.75***

0.5***

* p < 0.05 compared to placebo
** p < 0.001 compared to placebo
*** p < 0.0001 compared to placebo1 Intent-to-treat analysis2 Poisson regression model adjusted for center and time on study3 Logistic regression adjusted for center. Patients lost to follow-up
prior to an exacerbation were excluded from this analysis. (Analysis included
185, 183, and 184 patients for three times per week placebo, 22 mcg REBIF, and
44 mcg REBIF, respectively).4 Cox proportional hazard model adjusted for center5 ANOVA on ranks adjusted for center. Patients with missing scans
were excluded from this analysis.

The time to onset of progression in disability sustained
for three months was significantly longer in patients treated with REBIF than
in placebo-treated patients. The Kaplan-Meier estimates of the
proportions of patients with sustained disability are depicted in Figure 1.

The safety and efficacy of treatment with REBIF beyond 2
years have not been established.

Study 2 was a randomized, open-label, evaluator-blinded,
active comparator study. Patients with relapsing-remitting multiple
sclerosis with EDSS scores ranging from 0 to 5.5, and at least 2 exacerbations
in the previous 2 years were eligible for inclusion. Patients with secondary progressive
multiple sclerosis were excluded from the study. Patients were randomized to treatment
with three times per week subcutaneous injections of REBIF 44 mcg (n=339) or
once weekly intramuscular injections of 30 mcg AVONEX (n=338). Study duration
was 48 weeks.

The primary efficacy endpoint was the proportion of
patients who remained exacerbation-free at 24 weeks. The principal
secondary endpoint was the mean number per patient per scan of combined unique
active MRI lesions through 24 weeks, defined as any lesion that was T1 active or
T2 active. Neurological examinations were performed every three months by a
neurologist blinded to treatment assignment. Patient visits were conducted
monthly, and mid-month telephone contacts were made to inquire about
potential exacerbations. If an exacerbation was suspected, the patient was
evaluated with a neurological examination. MRI scans were performed monthly and
analyzed in a treatment-blinded manner.

Patients treated with REBIF 44 mcg three times per week
were more likely to remain relapse-free at 24 and 48 weeks than were patients
treated with AVONEX 30 mcg once per week (Table 5). This study does not support
any conclusion regarding effects on the accumulation of physical disability.

Table 5: Clinical and MRI Results from Study 2

REBIF 44 mcg

AVONEX 30 mcg

Absolute Difference

Risk of relapse on REBIF relative to AVONEX

Relapses

Proportion of patients relapse-free at 24 weeks1

N=339
75%*

N=338
63%

12%
(95% CI: 5%, 19%)

0.68
(95% CI: 0.54, 0.86)

Proportion of patients relapse-free at 48 weeks

62%**

52%

10%
(95% CI: 2%, 17%)

0.81
(95% CI: 0.68, 0.96)

MRI (through 24 weeks)

N=325

N=325

Median of the mean number of combined unique MRI lesions per patient per scan2 (25th, 75th percentiles)

PATIENT INFORMATION

REBIF (interferon beta-1a) Injection for Subcutaneous
Use

Read this Medication Guide before you start using REBIF
and each time you get a refill. There may be new information. The information
does not take the place of talking with your healthcare provider about your
medical condition or your treatment.

What is the most important information I should know
about REBIF?

REBIF can cause serious side effects. Tell your
healthcare provider right away if you have any of the symptoms listed below
while taking REBIF.

1. Behavioral health problems including depression and
suicidal thoughts. You may have mood problems including:

you are pregnant or plan to become pregnant. (It is not
known if REBIF will harm your unborn baby. Tell your healthcare provider if you
become pregnant during your treatment with REBIF.)

you are breastfeeding or plan to breastfeed. (It is not
known if REBIF passes into your breast milk. You and our healthcare provider
should decide if you will use REBIF or breastfeed. You should not do both.)

Tell your healthcare provider about all medicines you
take, including prescription and over-the-counter medicines, vitamins and
herbal supplements.

REBIF and other medicines may affect each other causing
side effects.

Ask your healthcare provider or pharmacist for a list of
these medicines, if you are not sure.

Know the medicines you take. Keep a list of them to show
your healthcare provider and pharmacist when you get a new medicine.

How should I use REBIF?

See the Instructions for Use at the end of this
Medication Guide on how to prepare and give an injection of REBIF using a
prefilled syringe. For the REBIF Rebidose autoinjector, read the Instructions
for Use that comes with the REBIF Rebidose autoinjector.

Your healthcare provider should show you how to prepare
and measure your dose of REBIF and how to inject your REBIF before you use it
for the first time.

REBIF is given by injection under the skin (subcutaneous
injection) on the same 3 days a week, for example, Monday, Wednesday and
Friday.

Your injections should be at least 48 hours apart. Take
them the same time each day.

Inject REBIF exactly as your healthcare provider tells
you.

Your healthcare provider will tell you how much REBIF to
inject, and may change the dose based on how your body responds. Do not inject
more than your healthcare provider tells you to.

Do not change your dose unless your healthcare provider
tells you to.

Change (rotate) your injection site you choose with each
injection. This will help decrease the chance that you will have an injection
site reaction.

Do not inject REBIF into an area of the body where
the skin is irritated, reddened, bruised, infected or scarred in any way.

REBIF comes as a:

prefilled syringe (REBIF)

single-use prefilled autoinjector (REBIF Rebidose
autoinjector)
Your healthcare provider will decide which is best for you. Always use a new,
unopened, prefilled syringe of REBIF or REBIF Rebidose autoinjector for each
injection. Do not reuse prefilled syringes or REBIF Rebidose
autoinjectors.

What are the possible side effects of REBIF?

REBIF may cause serious side effects, including:

See “What is the most important information I should
now about REBIF?”

Blood problems. REBIF can affect your bone marrow
and cause low red and white blood cell, and platelet counts. In some people,
these blood cell counts may fall to dangerously low levels. If your blood cell
counts become very low, you can get infections and problems with bleeding and
bruising. Your healthcare provider may ask you to have regular blood tests to
check for blood problems.

Seizures. Some people have had seizures while
taking REBIF.

The most common side effects of REBIF include:

flu-like symptoms. You may have flu-like symptoms when
you first start taking REBIF. You may be able to manage these flu-like symptoms
by taking over-the-counter pain and fever reducers. For many people, these
symptoms lessen or go away over time. Symptoms may include:

muscle aches

fever

tiredness

chills

stomach pain

change in liver blood tests

Tell your healthcare provider if you have any side effect
that bothers you or that does not go away.

These are not all the possible side effects of REBIF. For
more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects.
You may report side effects to the FDA at 1-800-FDA-1088.

How should I store REBIF?

Store REBIF in the refrigerator between 36°F to 46°F (2°C
to 8°C).

Do not freeze REBIF.

If you cannot refrigerate your REBIF, you can store your
REBIF at temperatures above 36°F and below 77°°F (2°C to 25°C) for up to
30 days.

Keep REBIF away from heat and light.

Keep REBIF and all medicines out of the reach of
children.

General information about the safe and effective use
of REBIF.

Medicines are sometimes prescribed for purposes other
than those listed in a Medication Guide. Do not use REBIF for a condition for
which it was not prescribed. Do not give REBIF to other people, even if they have
they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important
information about REBIF. If you would like more information, talk with your
healthcare provider. You may ask your healthcare provider or pharmacist for
information about REBIF that is written for healthcare professionals.

For more information, go to www.REBIF.com or call
toll-free 1-877-4473243.

Read and follow the Instructions for Use that come with
your REBIF prefilled syringe before you start using it can each time you get a
refill. Before you use a REBIF prefilled syringe for the first time, make sure
your healthcare provider shows you the right way to use it.

Important: For the REBIF Rebidose autoinjector,
read the Instructions for Use that come with the REBIF Rebidose autoinjector.

Parts of your REBIF Prefilled Syringe (See Figure A).

Figure A

Supplies needed for a REBIF
Injection (See Figure B):

REBIF prefilled syringe

alcohol pad or cotton balls and
rubbing alcohol

small adhesive bandage strip if
desired

puncture resistant safety
container for disposal of used syringes. See “Disposing of your Needles and
Syringes Section” in Step 4 of the IFU.

an over-the-counter pain or
fever reducing medicine, if your healthcare provider has recommended that you
take this before, at the same time, or after you give yourself REBIF to help
decrease the fever, chills, sweating and muscle aches (flu-like symptoms) that
may happen.

Figure B

Titration (Dosing) Schedule

When first starting treatment with REBIF, your healthcare
provider may prescribe either the 22 mcg or 44 mcg dose of REBIF. You should
gradually increase the dose over 4 weeks, starting at 20% of the prescribed
dose for the first 2 weeks, half-dose for the second 2 weeks (weeks 3 and 4),
and then the full dose prescribed by your healthcare provider.

If your prescribed dose is 22 mcg of REBIF, a REBIF
Titration Pack containing 6 prefilled syringes with 8.8 mcg and 6 prefilled
syringes with 22 mcg should be prescribed to you for use during the 4-week
starting period. Table 1 explains the amount to inject using the REBIF
Titration Pack syringes to gradually increase to 22 mcg.

Table 1: Titration Schedule for a 22 mcg Prescribed
Dose*

Week of Use

Syringe to Use

Amount of syringe

Week 1 Titration

8.8 mcg syringe

Use half of syringe

Week 2 Titration

8.8 mcg syringe

Use half of syringe

Week 3 Titration

22 mcg syringe

Use half of syringe

Week 4 Titration

22 mcg syringe

Use half of syringe

Week 5 and on

22 mcg syringe or autoinjector

Use full syringe or autoinjector

*Only prefilled syringes can be
used to titrate to the 22 mcg Prescribed Dose

If your prescribed dose is 44
mcg, you may be prescribed either a REBIF Titration Pack (described above) or
REBIF Rebidose Titration Pack containing 6 autoinjectors with 8.8 mcg and 6
autoinjectors with 22 mcg for use during the 4-week titration period. Table 2
explains the amount to inject using the REBIF Titration Pack or REBIF Rebidose
Titration Pack to gradually increase to 44 mcg.

Table 2: Titration Schedule
for a 44 mcg Prescribed Dose**

Week of Use

Syringe or Autoinjector to Use

Amount of syringe or autoinjector

Week 1 Titration

8.8 mcg syringe or autoinjector

Use full syringe or autoinjector

Week 2 Titration

8.8 mcg syringe or autoinjector

Use full syringe or autoinjector

Week 3 Titration

22 mcg syringe or autoinjector

Use full syringe or autoinjector

Week 4 Titration

22 mcg syringe or autoinjector

Use full syringe or autoinjector

Week 5 and on

44 mcg syringe or autoinjector

Use full syringe or autoinjector

**Prefilled syringes or
autoinjectors can be used to titrate to 44 mcg Prescribed Dose

Step 1. Preparing for your
REBIF Injection

Check the expiration date. Do
not use if the medication is expired. The expiration date is printed
on the syringe, plastic syringe packaging and carton.

Remove your REBIF syringe from
the refrigerator at least 30 minutes before you plan to use it so it can warm
to room temperature. Do not heat or microwave the medication.

Be sure that the dose, either,
8.8 mcg, 22 mcg or 44 mcg, described on the carton is the same as the dose
prescribed by your healthcare provider.

Remove the REBIF syringe from
the plastic packaging. Keep the needle capped.

Look at the contents of the
syringe carefully. The liquid should be clear to slightly yellow. Do not use
if the liquid is cloudy, discolored or contains particles. Use a
different syringe.

Step 2. Choose and Prepare
your Injection Site

The best sites for giving yourself an injection are those
areas with a layer of fat between the skin and muscle, like your thigh, the
outer surface of your upper arm, your stomach or buttocks.

Do not use the area near your waistline or within
2 inches of your navel. If you are very thin, use only the thigh or outer
surface of the arm for injection.

Use a different site each time you inject such as the
thigh, hip, stomach or upper arm (See Figure C)

Figure C

Do not inject REBIF into an area of your body
where the skin is irritated, reddened, bruised, infected or abnormal in any
way.

Wash your hands thoroughly with antibacterial soap before
preparing to inject the medicine.

Clean the injection site with an alcohol pad or cotton
ball with rubbing alcohol using a circular motion. To avoid stinging, you
should let your skin dry before you inject REBIF.

Step 3. Inject your REBIF

Remove the needle cap from the syringe needle.

If your healthcare provider has told you to use less than
the full 0.5 mL dose, slowly push the plunger in until the amount of medicine
left in the syringe is the amount healthcare provider told you to use.

Use your thumb and forefinger to pinch a pad of skin
surrounding the cleaned injection site (See Figure D). Hold the syringe like a
pencil with your other hand.

Figure D

While still pinching the skin, quickly insert the needle
like a dart at about a 90 degree angle (just under the skin) into the pad of
tissue as shown (See Figure E).

Figure E

After the needle is in, remove the hand that you used to
pinch your skin and inject the medicine using a slow, steady push on the
plunger until all the medicine is injected and the syringe is empty (See
Figure F)

Figure F

Withdraw the needle and apply gentle pressure to the
injection site with a dry cotton ball or sterile gauze. Applying a cold
compress or ice pack to the injection site after injection may help reduce
local skin reactions.

Put a small adhesive bandage strip over the injection
site, if desired.

Keep a record of the date and location of each injection.

After 2 hours, check the injection site for redness,
swelling, or tenderness. If you have a skin reaction and it does not clear up
in a few days, call your healthcare provider.

Step 4. Disposing of your Needles and Syringes

Put your used needles, syringes, and autoinjectors,
including REBIF, in an FDA-cleared sharps container right away after use. Do
not throw away (dispose of) any syringes or autoinjectors in your household
trash.
If you do not have an FDA-cleared sharps disposal
container, you may use a household container that is:

made of a heavy-duty plastic,

closed with a tight-fitting, puncture-resistant lid,

upright and stable during use,

leak-resistant, and

properly labeled to warn of hazardous waste inside the
container.

When your sharps disposal container is almost full, you
will need to follow your community guidelines for the right way to dispose of
your sharps disposal container. There may be state or local laws about how you
should throw away used autoinjectors and syringe needles. For more information
about safe sharps disposal, and for specific information about sharps disposal
in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.

Do not dispose of your used sharps disposal container in
your household trash unless your community guidelines permit this. Do not
recycle your used sharps disposal container.

This Medication Guide and Instructions for Use has
been approved by the U.S. Food and Drug Administration.